297P - Prognostic and predictive impact of NOTCH1 in early breast cancer

Background

The notch signalling pathway is considered to be an interesting prognostic and predictive marker in breast cancer as it is involved in proliferation, invasiveness and chemotherapy resistance.

Methods

From a prospective, multicenter cohort (Prognostic Assessment in Routine Application (PiA), 2009-2011, NCT01592825) of 1,270 breast cancer patients with a median follow-up of 60 months, the relative mRNA expression of NOTCH1 was determined in 414 tumour samples by qPCR. The primary objective was the evaluation of NOTCH1 mRNA expression and its association with patients and tumour characteristics. The secondary objectives were the associations with recurrence-free interval (RFI), overall survival (OS), and the predictive value of NOTCH1 mRNA expression with regard to adjuvant chemotherapy.

Results

Within our study, high NOTCH1 expression was detected in one-third of the tumours. We observed a significant prognostic impact of high NOTCH1 expression with regard to RFI (adjusted hazard ratio 2.1, 95% CI 1.077–4.118). Patients with high NOTCH1 expression and chemotherapy (n = 86) had a worse clinical outcome compared to those without chemotherapy with an adjusted 3.1 higher risk for disease-related events (RFI events, 95% CI 1.321–7.245, p = 0.009).

Conclusions

In summary, in our cohort for NOTCH1 we showed a prognostic and, particularly, a significant predictive impact. We observed that tumours with high NOTCH1 expression seem to be less sensitive to cytotoxic treatment. Therefore, we postulate, that downregulation of the Notch signalling pathway, e.g. with y-secretase inhibitors, may improve the efficacy of breast cancer therapy by restoring chemosensitivity.

Clinical trial identification

NCT01592825 (release date: 16.12.2009).

Editorial acknowledgement

Legal entity responsible for the study

E. Kantelhardt, M.Vetter.

Funding

Wilhelm Roux Program of the Medical Faculty, Martin Luther University Halle-Wittenberg (grant number: FKZ 25/36); German Federal Ministry of Education and Research (grant number: Med FKZ 031A429).

Disclosure

C. Thomssen: Financial Interests, Personal, Speaker, Consultant, Advisor: Amgen, AstraZeneca, Aurikamed, Daiichi Sankyo, Gilead, Jörg Eickeler, Hexal, Lilly, Medupdate, MSD, Nanostring, Novartis, Onkowissen, Pfizer, Roche, Seagen, Vifor; Financial Interests, Personal, Financially compensated role: Forum Sanitas; Non-Financial Interests, Personal, Member: AGO Breast Committee, ASCO, DGGG (Germ Soc OB/GYN), DGS (Germ Soc Senology), DKG (Germ Cancer Soc), EORTC PathoBiomarker Group; Non-Financial Interests, Personal, Member of Board of Directors: AGO - B Breast Study Group ; Non-Financial Interests, Personal, Officer: BIG; Non-Financial Interests, Personal, Invited Speaker: ESO; Non-Financial Interests, Personal, Steering Committee Member: ESMO. All other authors have declared no conflicts of interest.